A catalytic antibody discovery made at The Scripps Research Institute has formed the basis of the upcoming acquisition of biotechnology venture CovX by pharmaceutical giant Pfizer, Inc.

"I am deeply gratified that our scientific findings have found such a broad potential application for drug discovery," said Richard A. Lerner, president of Scripps Research. "This development underlines the importance of basic science for advancing human health. When the initial discoveries were made, no one envisaged their ultimate therapeutic potential."

As licensor of the technology, Scripps Research will receive a percentage of the proceeds from the sale, as well royalties from any resulting therapies. The transaction between CovX and Pfizer was announced by the companies on December 18 and is expected to be completed in the first quarter of 2008.

The Catalytic Antibody Advantage

Empowered by compelling results in his laboratory's development of a new class of drugs, Professor Carlos F. Barbas, III, Ph.D., set out to found CovX in 2002. He teamed up with his colleague Richard Lerner, with whom he had developed a unique and powerful class of catalytic antibodies.

This work offers a groundbreaking way to physically combine catalytic antibodies, which are large, soluble molecules that remain in the body for long periods of time, with small molecule drugs and peptides, which can kill disease-causing cells but may be expelled from the body too quickly to be effective as a therapy. These hybrid molecules have the desirable properties of each—killing disease-causing cells and staying in circulation long enough to dramatically enhance the drug's effectiveness.

The approach, which the scientists call "chemically programmed antibodies," has led to a number of compounds against cancer and metabolic disease under development by CovX. Chemically programmed antibodies, or "CovX-Bodies" as they were named by CovX, could also offer a general method for developing therapies against a range of diseases.

This technology represents the first time catalytic antibodies have been used in human therapy.

Building on Basic Science

Catalytic antibodies—which Lerner pioneered simultaneously with Scripps Research Professor Peter Schultz, Ph.D., (then at the University of California, Berkeley) in the 1980s—are large proteins naturally produced by the immune system and found in the bloodstream.

Unlike ordinary antibodies, which recognize a wide range of foreign pathogens (such as bacteria and viruses) then alert the immune system to the presence of the invaders, catalytic antibodies recognize the transition state for chemical reactions. Catalytic antibodies can also catalyze chemical reactions, similar to enzymes.

These special properties of catalytic antibodies open the door to some interesting chemistry.

Take Barbas, Lerner, and then-postdoctoral fellow Jurgen Wagner's paper published in the December 15, 1995 (Vol. 270) issue of the journal Science, which laid the foundation for the CovX technology years later.

In the study, the scientists used a technique called reactive immunization, which enabled antibodies to catalyze reactions previously thought impossible. Specifically, the technique allowed scientists to use antibodies to catalyze carbon-carbon bond formation and to bind catalytic antibodies to antigens covalently. (In general, antibodies bind non-covalently with their substrates.)

"The key feature of the reactive immunization approach is that it allowed us to define in rather precise chemical detail the amino acids within the active site of the antibody that would perform the chemical reaction," said Barbas, adding that the antibodies the team developed with reactive immunization remain the most highly active catalysts ever made.

The paper was a broad step forward in basic science.

Putting the Pieces Together

But an idea for a powerful application wasn't too far behind.

To illustrate the reactive immunization work during presentations to students and colleagues, Barbas created a simple slide. The image showed the mechanism of the catalytic activity. In chemical terms, it showed an R group attached to a b diketone. The b diketone, Barbas would note in his talks, leads to self-assembly of the substrate and antibody to form a complex.

In another project in the Barbas laboratory, the scientists happened to be exploring the potential of antibodies in cancer therapy. Because of this work, Barbas was aware that many pharmaceutical companies had tried to develop compounds against integrin molecules (a large and important family of adhesion molecules that promote stable interactions between cells and their environment), but that these projects had all run up against the same roadblock.

While potential therapeutics bound to the cancer integrin molecules with high affinity and specificity, the compounds were quickly cleared from the body—in some cases, in as short a period as 15 minutes. Especially for a chronic indication such as cancer, this rendered the compounds impractical for use as drugs, because they were difficult to administer often enough or in large enough quantities to produce a therapeutic effect.

Then one day, looking at the slide he had used for years in describing reactive immunization, Barbas suddenly got an idea. He saw a way to put together one of these integrin-targeting drugs with a catalytic antibody.

"Looking back at the slide, I thought, 'What if I just took that small molecule from the literature that binds these integrins, and put a diketone on it. If it attaches itself to the antibody, it would circulate for a long time."

1,000-Fold Increase in Therapeutic Effect

In the lab, Barbas, Lerner, and colleagues discovered that the molecules in question indeed self-assembled to form a potent and long-lasting therapeutic agent.

This proof-of-principal work was published in the journal Proceedings of the National Academy of Sciences (Vol. 100, No. 9, April 29, 2003). Intriguingly, the scientists reported that they were able to induce the self-assembly of the complex not only by combining the two substances in the test tube before administration, but also by injecting the two compounds separately into the bloodstream of a mouse, where the compounds found each other and self-assembled into the desired complex.

In both cases, the hybrid molecules had a profound effect on the size of tumors in mouse models—shrinking tumors of both Kaposi's sarcoma and colon cancer.

"We were able to show the chemically programmed complex had at least 1,000-fold increase in the therapeutic effect compared with the small molecule alone," said Barbas. "With that came the idea that is this too powerful an approach not to push into human studies."

By the time the study was published, Barbas and Lerner had founded CovX, a privately held company with offices in Dublin, Ireland, and San Diego, CA, to do just that.

Today, two of the hybrid compounds under development by CovX have completed preclinical work with promising results as anti-tumor agents and have been approved for testing in humans. The compound the company calls CVX-045 is currently finishing Phase I trials. CVX-060 is poised to enter Phase 1 trials this month. A third compound to treat diabetes is close behind. By the end of next year, four novel drugs should be in clinical testing. "The Pfizer acquisition will allow us to fully realize the potential of this approach. Within five years we hope to have more than a dozen new drugs in clinical testing," said Barbas

"It has been a dream of mine to develop drugs that make a difference," said Barbas. "I couldn't be more excited by these developments."

Broad Practical Advantages

Above and beyond the compounds CovX currently has in development, chemically programmed antibodies could offer a method for developing therapeutics to fight a broad range of diseases.

"A single antibody can become a whole multiplicity of therapeutics simply by mixing it with the desired small molecule or peptide," said Barbas. "It's a kind of engine to make drugs, which is typically hard to find. It's a whole new and counterintuitive way to look at antibodies."

This approach also offers a number of practical advantages for drug development, which could prove key given the economic realities facing the pharmaceutical industry.

The first advantage is that chemically programmed antibodies offer the possibility of rescuing the hundreds of compounds that exist which were initially developed as drugs, but then later abandoned due to problems arising from a short half-life in the bloodstream. Alternatively, the technique could provide killing function to compounds that bind to diseased cells but that did not inflict sufficient damage to be developed into therapies.

Another upside to the chemically programmed antibody approach is that it could speed drug development and reduce the cost of bringing these drugs to market. In contrast to developing specific antibodies against each target, developing only one protein therapeutic, then mixing it with a new small molecule or peptide, enables the antibody to be optimized once, then produced on a large scale.

The recent decision to seek buyers for CoxX was spurred in part by the realization of the huge potential of the chemically programmed antibody approach, and the financing required to fully realize that potential.

"I am deeply gratified that our scientific findings have found such a broad potential application for drug discovery. This development underlines the importance of basic science for advancing human health."